Neutrophil‐to‐monocyte ratio is the better new inflammatory marker associated with rheumatoid arthritis activity

Abstract Background Rheumatoid arthritis (RA) is a systemic autoimmune disease that chronically affects patients with episodes of inflammation. New inflammatory hematological markers were investigated for follow‐up, such as the neutrophil–monocyte ratio (NMR), lymphocyte monocyte ratio (LMR), and neutrophil–lymphocyte ratio (NLR). This study was conducted to determine the most useful marker based on studies of association with RA disease activity and correlation with the classical markers C‐reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF). Methods This case‐control study included 62 chronic RA patients who had previously been diagnosed and experienced episodes of symptoms while attending a variety of public and private rheumatology clinics in Ibb City, Republic of Yemen, for the period of September 1 to November 30, 2021. Twenty healthy volunteers were included in this study. Complete blood count, CRP, ESR, and RF levels were measured in all participants. Results The total leukocyte count, neutrophil count, platelet count, NMR, LMR, and NLR were positively correlated with CRP and ESR, but the monocyte count was reversed. The area under the curve (AUC = 0.861, 95% confidence interval [CI] = 0.769–0.948) for the NMR cutoff value of 4.7 was equal to that of CRP and close to that of ESR. This NMR cutoff value had 87% sensitivity and 80% specificity. LMR and NLR cutoff values of 4.35 and 1.35, respectively, resulted in AUCs of (AUC = 0.807, 95% CI, 0.708–0.905) and (AUC = 0.699, 95% CI, 0.571–0.819); their sensitivity and specificity were 62.3%, 90%, 57.4%, and 80%, respectively. Conclusions As a convenient and low‐cost inflammatory marker of RA activity, NMR outperformed LMR and NLR.


| INTRODUCTION
Rheumatoid arthritis (RA) is a systemic autoimmune rheumatic disease that affects the synovium of joints, causing inflammation, bone damage, and finally disability. 1 The cardinal pathogenic hallmark of RA is inflammation that manifests disease activity, Inflammation aggravates and subsides alternately, causing fluctuations in the RA disease course; therefore, rapid suppression of inflammation maximizes disease control. 2 Thus, pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-15, IL-18, and tumor necrosis factor-α (TNF-α), initiate changes represented by the characteristic signs of inflammation (redness, swelling, pain, and the perception of surface and internal heat). In contrast, some other cytokines, such as IL-4 and IL-10, act as anti-inflammatory agents. 3,4 Pro-inflammatory cytokines mediate the formation of inflammatory edema, which is responsible for the development of stiffness symptom. 5 Potential prognostic markers for assessing RA disease activity had been investigated earlier, including the classical inflammatory markers, rheumatoid factors (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) that are widely used as indicators of disease activity. 6,7 Other markers that had been investigated in RA patients and showed significantly higher serum levels in patients compared with healthy controls are high-sensitivity CRP, IL-6, TNF-α, and IL-10. 8 Neutrophils, monocytes, lymphocytes, and platelets have been known to contribute to the development and progression of inflammation 9 The neutrophil-to-monocyte ratio (NMR), lymphocyte-to-monocyte ratio (LMR), and neutrophil-to-lymphocyte ratio (NLR) have drawn attention in recent years as a novel, simple, and inexpensive inflammatory markers for many diseases, including RA. [10][11][12][13] Accordingly, this study was conducted to assess the most useful of the new markers NMR, LMR, and NLR based on their degree and significance of association with RA disease activity, and their correlation with the classical markers CRP, ESR, and RF.

| Laboratory analysis results
Laboratory investigations of RA patients and healthy controls showed a statistical difference in the majority of them, as shown in Table 3

| Correlation between the new and classic inflammatory markers
Correlation studies reveal statistically significant weak and moderate correlations listed in Table 4    All patients enrolled in this study attended rheumatology clinics while suffering from RA symptoms such as joint pain, swelling, warmth, stiffness, and movement problems as listed in Table 2 The usefulness of NMR as an inflammatory marker was reported previously. NMR is significantly associated with active ulcerative colitis disease-another inflammatory disease-and may be used in differentiating active from remission states. 23 Elevated NMR was associated with poor prognosis in patients with pancreatic cancer. 24

ACKNOWLEDGMENTS
Thank you to Afnan Al; Khateeb, Amat Alrahman Sufian, Eman AlGasha'a, Aisha Alshelh, and Maria Asakaf for their assistance. The authors did not receive any funds.

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict interest.

DATA AVAILABILITY STATEMENT
All data is available in this manuscript.

ETHICS STATEMENT
Informed consent for participation in the study was obtained from patients. This work met the international ethical guidelines, mainly the WMA Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects, 2013.

TRANSPARENCY STATEMENT
The lead author Jamil M. A. S. Obaid affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.